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Central nervous system-associated macrophages modulate the immune response following stroke in aged mice
Damien Levard1, Célia Seillier1, Mathys Bellemain-Sagnard1
1Normandie University, UNICAEN, Université Caen Normandie, INSERM UMR-S U1237, Physiopathology and Imaging of Neurological Disorders (PhIND), GIP Cyceron, Institut Blood and Brain @ Caen-Normandie (BB@C), Caen, France.
Abstract:
Age is a major nonmodifiable risk factor for ischemic stroke. Central nervous system-associated macrophages (CAMs) are resident immune cells located along the brain vasculature at the interface between the blood circulation and the parenchyma. By using a clinically relevant thromboembolic stroke model in young and aged male mice and corresponding human tissue samples, we show that during aging, CAMs acquire a central role in orchestrating immune cell trafficking after stroke through the specific modulation of adhesion molecules by endothelial cells. The absence of CAMs provokes increased leukocyte infiltration (neutrophils and CD4+ and CD8+ T lymphocytes) and neurological dysfunction after stroke exclusively in aged mice. Major histocompatibility complex class II, overexpressed by CAMs during aging, plays a significant role in the modulation of immune responses to stroke. We demonstrate that during aging, CAMs become central coordinators of the neuroimmune response that ensure a long-term fine-tuning of the immune responses triggered by stroke.
Insights
Aging alters central nervous system-associated macrophages (CAMs), crucial immune cells in the brain. These aged CAMs orchestrate immune cell movement after stroke, impacting neurological function and leukocyte infiltration.
Area of Science:
- Neuroscience
- Immunology
- Gerontology
Background:
- Age is a significant nonmodifiable risk factor for ischemic stroke.
- Central nervous system-associated macrophages (CAMs) are resident brain immune cells residing along the vasculature.
- Understanding age-related changes in neuroimmune responses post-stroke is critical.
Purpose of the Study:
- To investigate the role of aging in CAMs' function after ischemic stroke.
- To elucidate how CAMs modulate immune cell trafficking in aged versus young individuals post-stroke.
- To identify key molecular mechanisms, like Major Histocompatibility Complex class II (MHC-II), involved in aged CAMs' immune regulation.
Main Methods:
- Utilized a clinically relevant thromboembolic stroke model in young and aged male mice.
- Analyzed corresponding human brain tissue samples.
- Examined the impact of CAM absence on leukocyte infiltration and neurological deficits.
- Assessed the expression of Major Histocompatibility Complex class II (MHC-II) on CAMs.
Main Results:
- Aging significantly alters CAMs' role in orchestrating immune cell trafficking post-stroke.
- Absence of CAMs led to increased leukocyte infiltration and neurological dysfunction specifically in aged mice.
- Overexpression of MHC-II by aged CAMs plays a crucial role in modulating the neuroimmune response to stroke.
- CAMs coordinate long-term immune responses following stroke, particularly in aged individuals.
Conclusions:
- Aged CAMs are central coordinators of the neuroimmune response after ischemic stroke.
- CAMs' modulation of endothelial adhesion molecules is key to regulating immune cell entry into the brain post-stroke.
- Targeting aged CAMs and their associated pathways, like MHC-II, may offer therapeutic strategies for stroke in the elderly.
